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| United States Patent |
5,214,040
|
|
Cuberes-Altisent
, et al.
|
May 25, 1993
|
Nonsaditive antihistaminics derived from benzimidazoles
Abstract
The present invention relates to novel benzimidazole derivatives
characterized in that they are of the general formula I, and their
therapeutically acceptable salts,
##STR1##
in which: R.sub.1 and R.sub.2, which are identical or different, represent
a hydrogen or a halogen atom, a lower alkyl radical, a hydroxyl radical,
an alkoxy radical, an alkyl carboxylate radical, or an aryl or substituted
aryl radical,
n may take the values 0 or 1,
m may take the values 2 to 4,
X, Y, Z and W, which are identical or different, and which may even form
part of another aromatic or nonaromatic ring, represent a nitrogen atom or
a carbon atom linked to a hydrogen or to a halogen atom, or to another
alkyl, aryl, carboxyalkyl, carboxylic, hydroxyl, alkyl hydroxyl, sulphonic
or alkylsulphonic radical.
| Inventors:
|
Cuberes-Altisent; Maria R. (Barcelona, ES);
Frigola-Constansa; Jordi (Barcelona, ES);
Pares-Corominas; Juan (Barcelona, ES)
|
| Assignee:
|
Laboratorios del Dr. Esteve, S.A. (Barcelona, ES)
|
| Appl. No.:
|
863208 |
| Filed:
|
April 3, 1992 |
Foreign Application Priority Data
| Current U.S. Class: |
514/218; 540/575 |
| Intern'l Class: |
A61K 031/55; C07D 403/14 |
| Field of Search: |
540/575
514/218
|
References Cited
U.S. Patent Documents
| 4200641 | Apr., 1980 | Vandenberk et al. | 424/267.
|
| 5010075 | Apr., 1991 | Pascal et al. | 540/575.
|
Primary Examiner: Morris; Patricia L.
Attorney, Agent or Firm: Dressler, Goldsmith, Shore, Sutker & Milnamow
Claims
We claim:
1. A compound derived from benzimidazole characterized in that it is of the
formula I, and its therapeutically acceptable salts.
##STR14##
in which: R.sub.1 and R.sub.2, which are identical or different, represent
a hydrogen or a halogen atom, a lower alkyl radical, or a hydroxyl
radical,
n may take the values 0 or 1,
m may take the values 2 to 4,
X, Y, Z and W, which are identical or different, represent a nitrogen atom
or a carbon atom linked to a hydrogen or to a halogen atom, or to another
lower alkyl, hydroxyl, or sulphonic acid radical, or to a carboxyl or
alkoxycarbonyl radical having up to two carbon atoms in its alkoxy
position.
2. A compound which is chosen from the following group:
1-(2-ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl-methyl}ben
zimidazole,
1-(2-ethoxyethyl)-2-{4-[4-pyrrol-1-yl)butyl]homopiperazin-1-yl-methyl}benzi
midazole,
1-(2-ethoxyethyl)-2-{4-[4-(4,5-dichloro-2-methylimidazole-1-yl)butyl]homopi
perazin-1-yl-methyl}benzimidazole,
1-2(ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl}benzimidazo
le,
1-(2-ethoxyethyl)-2-{4-[4-(4-carboxypyrazole-1-yl)butyl]homopiperzin-1-yl}b
enzimidazole,
1-(2-ethoxyethyl)-2-{4-(4-ethyloxycarbonylpyrazole-1-yl)butyl]homopiperazin
-1-yl}benzimidazole.
3. A pharmaceutical composition characterized in that it contains, in
addition to a pharmaceutically acceptable carrier, at least one derivative
of formula I or one of its physiologically acceptable salts, according to
one of claim 1 or 2.
Description
The present invention relates to novel benzimidazole derivatives, to their
method of preparation and to their use as medicinal products.
The compounds which are the subject of the present invention are of the
general formula I
##STR2##
in which: R.sub.1 and R.sub.2, which are identical or different, represent
a hydrogen or a halogen atom, a lower alkyl radical, a hydroxyl radical,
an alkoxy radical, an alkyl carboxylate radical, or an aryl or substituted
aryl radical,
n may take the values 0 or 1,
m may take the values 2 to 4,
X, Y, Z and W, which are identical or different, and which may even form
part of another aromatic or nonaromatic ring, represent a nitrogen atom or
a carbon atom linked to a hydrogen or to a halogen atom, or to another
alkyl, aryl, carboxyalkyl, carboxylic, hydroxyl, alkylhydroxyl, sulphonic
and alkylsulphonic radical.
Benzimidazole derivatives are already known in the scientific literature
which possess various biological activities such as for example analgesic
and anti-inflammatory activities (Japan Kokai 75, 126, 682), anti-gastric
secretion activity (EP 246,126 and EP 5129); antihistaminic activity (J.
Jilek et al., Collect. Czech. Chem. Commun. 1988, 53, 870-83; U.S. Pat.
No. 4,200,641; Drugs of the Future, VII; 10-1, 1982; R. Iemura et al., J.
Med. Chem., 1986, 29, 1178-1183; R. Iemura et al., J. Heteroxycyclic.
Chem., 1987, 24, 31-37; French Patent Application FR 90/09563). The
compounds which are the subject of the present invention are novel
benzimidazole derivatives, namely
1-(2-ethoxyethyl)-2-{.omega.[.omega.(azol-1
-yl)alkyl]exahydro-1,4-diazepin-1-ylalkyl}benzimidazole, which will be
named in this invention as
1-(2-ethoxyethyl)-2-{.omega.[.omega.(azol-1-yl)alkyl]homopiperazin-1-ylalk
yl}benzimidazole. We have discovered that these novel derivatives possess a
very good antihistaminic activity and have no side effects on the central
nervous system.
The novel derivatives of general formula I may be prepared, in accordance
with the invention, using any one of the following methods:
Method A
By reacting a compound of general formula IIa
##STR3##
in which R.sub.1, R.sub.2, n and m have the meanings given above, and A
represents a halogen atom or a good "departing group" chosen from tosyloxy
or mesyloxy, with a compound of general formula III
##STR4##
in which X, Y, Z and W have the meanings given above.
The reaction is carried out in the presence of a suitable solvent, for
example dimethyl sulphoxide, dimethylformamide, alcohols, aromatic or
nonaromatic hydrocarbons, ethers such as dioxane or diphenyl ether, or of
mixtures of these solvents. This reaction is advantageously carried out in
the presence of a base such as alkali metal hydroxides, carbonates, or
bicarbonates, or alternatively of a mixture of these bases. Alkali metal
hydrides may also be used. The most suitable temperatures vary between
room temperature and the reflux temperature of the solvent, and the
reaction time is between 1 hour and 24 hours.
Method B
By reacting a compound of general formula IIa, in which A represents a
radical --NH.sub.2, with 2,5-dimethoxytetrahydrofuran.
The reaction is carried out in the presence of a suitable solvent, for
example acetic acid, water, alcohols, ketones or of mixtures of these
solvents. The most suitable temperatures vary between room temperature and
the reflux temperature of the solvent, and the reaction time is between a
few minutes and 24 hours.
Method C
By reacting a compound of general formula IV
##STR5##
in which R.sub.1, R.sub.2 and n have the meanings given above, with a
compound of general formula V
##STR6##
where X, Y, Z, W and m have the meanings given above, and B represents a
halogen atom or a good "departing group" chosen from tosyloxy or mesyloxy.
The reaction is carried out in the presence of a suitable solvent, for
example, dimethyl sulphoxide, dimethylformamide, alcohols, aromatic or
nonaromatic hydrocarbons, ethers such as dioxane or diphenyl ether, or of
mixtures of these solvents. This reaction is advantageously carried out in
the presence of a base such as alkali metal hydroxides, carbonates or
bicarbonates, or alternatively of a mixture of these bases. The most
suitable temperatures vary between room temperature and the reflux
temperature of the solvent, and the reaction time is between 1 hour and 24
hours.
The preparation of the novel derivatives according to the invention is
given in the, following examples. The examples below, given simply by way
of illustration, should not, however, limit in any manner the scope of the
invention.
Method A
Example 1
Preparation of
1-(2-ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-ylmethyl}ben
zimidazole
a) 1-(2-ethoxyethyl)-2-(4-benzyl-1H-homopiperazin-1-ylmethyl)benzimidazole.
A solution of 13.6 g (42.5 mmol) of
1H-2-((4-benzyl-1H-homopiperazin-1-yl-methyl)benzimidazole in 20 ml of
dimethylformamide (DMF) is slowly added to a suspension of 2.04 g (46.7
mmol) of NaH (55% in mineral oil). The mixture is heated to
60.degree.-70.degree. C. for 1 hour, and a solution of 5.1 g (46.7 mmol)
of 1-chloro-2-ethoxyethane in 5 ml of DMF is then added.
The mixture is maintained stirring, under the same conditions for 5 hours.
It is poured into water and extracted with ethyl acetate, washed with
water, the organic phase dried using Na.sub.2 SO.sub.4, filtered and
evaporated. The resulting oil is purified on a silica chromatography
column. Elution with chloroform-methanol 99:1 gives 5.65 g (50%) of
1-(2-ethoxyethyl-2-(4-benzyl-1H-homopiperazin-1-yl-methyl)benzimidazole,
and elution with chloroform-methanol 97:3 gives 4.3 g (32%) of unreacted
starting product.
.sup.1 H-NMR (CDCl.sub.3): .delta.1.12 (t,3 H); 1.79 (m,2 H); 2.69 (m,8 H);
3.41 (q,2 H); 3.63 (s,2 H); 3.76 (t,2 H); 3.98 (s,2 H); 4.55 (t,2 H); 7.25
(m,8 H); 7.7 (m,1H).
b) 1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole.
A solution of 5.94 g (15.15 mmol) of
1-(2-ethoxyethyl)-2-(4-benzyl-1H-homopiperazin-1-yl-methyl)benzimidazole
in 80 ml of 80% acetic acid is heated at 60.degree. C. with 4.02 g of 5%
Pd/C (water content: 50%) under a 5 atm. hydrogen atmosphere, for 16
hours. The mixture is filtered and evaporated to dryness. The residue is
taken up in chloroform and washed with 20% NaOH, with water, and dried
using Na.sub.2 SO.sub.4, filtered and evaporated. 3.65 g (80%) of
1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole are obtained.
.sup.1 H-NMR (CDCl.sub.3); .delta.1.12 (t,3 H); 1.78 (m,2 H); 2.28 (broad
s, 1H); 2.74-3.05 (m,8 H); 3.41 (q,2 H); 3.76 (t,2 H); 4.02 (s,2 H); 4.56
(t,2 H); 7.25 (m,3 H); 7.7 (m,1H). IR(film): 3312, 1463, 1119, 744
cm.sup.-1
c)
1-(2-ethoxyethyl)-2-(8-methylaza-5-azoniaspiro[4.6]undecane)benzimidazole.
A mixture of 4 g (13.24 mmol) of
1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole, 3.29 g
(15.23 mmol) of 1,4-dibromobutane and 2.5 g (18.1 mmol) of potassium
carbonate in 40 ml of chloroform, is refluxed for 16 hours. The mixture is
cooled, filtered and evaporated. The residue is triturated in ethyl ether
and 5.6 g (97%) of a hygroscopic solid are obtained, which solid is used
as it is without further purification.
.sup.1 H-NMR(CDCl.sub.3): .delta.1.06 (t,3 H); 2.24 (m,6 H); 2.96-3.51 (m,8
H); 3.72-3.90 (m,8 H); 4.15 (s,2 H); 4.53 (t,2 H); 7.30 (m,3 H); 7.74
(m,1H).
d)
1-(2-ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl-methyl}be
nzimidazole.
A mixture of 3 g (6.86 mmol) of
1-(2-ethoxyethyl)-2-(8-methylaza-5-azoniaspiro[4.6]undecane)benzimidazole
bromide, 0.56 g (8.24 mmol) of pyrazole, 1.8 g (13 mmol) of potassium
carbonate and 30 ml of dimethylformamide is refluxed for 16 hours. The
mixture is cooled, filtered and the filtrate is evaporated to dryness. The
residue is taken up in chloroform and washed with water. The organic phase
is dried using Na.sub.2 SO.sub.4, filtered and evaporated. The resulting
oil is purified on a silica chromatography column (eluent:
chloroform-methanol 9:1). 1.40 g (48%) of
1-(2-ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl-methyl}be
nzimidazole are thus obtained in oil form.
The spectroscopic data for its identification are presented in Tables 1 and
2.
Example 3
Preparation of
1-(2-ethoxyethyl)-2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]homopi
perazin-1-yl-methyl}benzimidazole
The preparation is carried out in a manner quite similar to that presented
in Example 1, with a yield of 36%.
The spectroscopic data for its identification are presented in Tables 1 and
2.
Example 5
Preparation of
1-(2-ethoxyethyl)-2-{4-[4-(4-carboxypyrazol-1-yl)butyl]homopiperazin-1-yl}
benzimidazole
a) 1-(2-ethoxyethyl)-2-(8-aza-5-azoniaspiro[4.6]-undecane)benzimidazole.
The preparation is carried out using the same procedure as that presented
in Example 1c, with a yield of 97%.
.sup.1 H-NMR (CDCl.sub.3): .delta.1.09 (t,3 H); 1.9-2.4 (m,6 H); 3.42 (q,2
H); 3.82 (t,2 H); 3.9-4.1 (m,12 H); 4.26 (t,2 H); 7.20 (m,3 H); 7.50
(m,1H).
b)
1-(2-ethoxyethyl)-2-{4-[4-(4-ethyloxycarbonylpyrazol-1-yl)butyl]homopipera
zin-1-yl}benzimidazole.
The preparation is carried out using the same procedure as that presented
in Example 1d, and the crude product is obtained, which is purified on a
silica chromatographic column (eluent:chloroform-methano195:5). Yield 35%.
.sup.1 H-NM2 (CDCl.sub.3): .delta.1.13 (t,3 H); 1.33 (t,3 H); 1.93 (m,6 H);
2.6 (t,2 H); 2.8 (m,4 H); 3.35-3.82 (m,8 H); 4.07-4.4 (m,6 H); 7.1-7.25
(m,3 H); 7.5 (m,1H); 7.85 (s,2 H).
The ester prepared above is hydrolysed by treating a solution in ethanol
with 10% sodium hydroxide for 15 hours at room temperature. The alcohol is
evaporated and the aqueous solution is neutralised with hydrochloric acid.
It is evaporated to dryness and the acid is extracted from the residue by
digestion with isopropanol. Yield 87%. Melting point >300.degree. C.
The spectroscopic data for its identification are presented in Tables 1 and
2.
Method B
Example 2
Preparation of
1-(2-ethoxyethyl)-2-{4-[4-(pyrrol-1-yl)butyl]homopiperazin-1-yl-methyl}ben
zimidazole
A solution of 2.98 g (8 mmol) of
1-(2-ethoxyethyl)-2-{4-(4-aminobutyl)homopiperazin-1-yl-methyl}benzimidazo
le and 1.06 g (8 mmol) of 2,5-dimethoxytetrahydrofuran hydrofuran in 30 ml
of acetic acid is refluxed for 25 minutes. The mixture is cooled, poured
into ice cold water, neutralised with NaHCO.sub.3 and extracted with
chloroform. It is dried using Na.sub.2 SO.sub.4 and evaporated to dryness
under vacuum. 3.2 g of the crude compound are thus obtained which are
purified on a silica chromatography column (eluent: chloroform-methanol
92:8). Yield 51%.
The spectroscopic data for the compound are the same as those presented in
Example 2 of method C.
Method C
Example 2
Preparation of 1-(2-ethoxyethyl)-2
{4-[4-(pyrrol-1-yl)butyl]homopiperazin-1-yl-methyl}benzimidazole
A mixture of 2.42 g (8 mmol) of
1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole, 1.39 g (8.8
mmol) of 1-(4-chlorobutyl)pyrrole, 1.65 g (12 mmol) of potassium carbonate
and 1.65 g (11 mmol) of sodium iodide in 40 ml of methyl ethyl ketone is
refluxed for 16 hours. The mixture is cooled, filtered and the filtrate
evaporated to dryness. The residue is taken up in chloroform and washed
with water, dried, filtered and evaporated under vacuum. The resulting
product is purified on a silica chromatographic column (eluent:
chloroform-methanol 92:8) and 1.9 g (56%) of
1-(2-ethoxyethyl)-2-{4-[4-(pyrrol-1-yl)butyl]homopiperazin-1-yl-methyl}ben
zimidazole are obtained.
The spectroscopic data for its identification are presented in Tables 1 and
2.
Example 4
Preparation of
1-(2-ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl}benzimida
zole
The preparation is carried out in a manner quite similar to the procedure
in the example above, and the compound, whose salt with maleic acid has a
melting point of 102.degree.-105.degree. C., is obtained with a yield of
49%.
TABLE I
__________________________________________________________________________
##STR7##
Example IR (cm.sup.-1)
no. R.sub.1
R.sub.2
n m R Method
(film)
__________________________________________________________________________
1 H H 1 4
##STR8## A C 2938, 2869, 1464, 1119, 748, 619
2 H H 1 4
##STR9## B C 2936, 2870, 1463, 1120, 745, 725
3 H H 1 4
##STR10##
A 2937, 1464, 1408, 1246 1120, 746
4 H H 0 4
##STR11##
C maleate (KBr): 3000, 2890, 1619, 1579, 1470,
1358
5 H H 0 4
##STR12##
A 3600-3150, 1571, 1432, 670
6 H H 0 4
##STR13##
A 1715, 1565, 1465, 1120, 1040,
__________________________________________________________________________
750
TABLE 2
______________________________________
Example .sup.1 H-NMR (CDCl.sub.3)
no. .delta.
______________________________________
1 1.11(t, 3H); 1.41(m, 2H); 1.79(m, 4H); 2.37-2.74
(m, 10H); 3.39(q, 2H); 3.75(t, 2H); 3.96(s, 2H);
4, 12(t, 2H); 4.55(t, 2H); 6.22(broad s, 1H);
7.2-7.47(m, 5H); 7.68(m, 1H)
2 1.11(t, 3H); 1.47(m, 2H); 1.82(m, 4H); 2.48
(t, 2H); 2.73(m, 8H); 3.39(q, 2H); 3.75(t, 2H);
3.87(t, 2H); 3.97(s, 2H); 4.53(t, 2H); 6.11(m, 2H);
6.63(m, 2H); 7.25(m, 3H); 7.67(m, 1H)
3 1.11(t, 3H); 1.5-1.9(m, 6H); 2.36(s, 3H);
2.5-2.9(m, 10H); 3.39(q, 2H); 3.7-3.9(dt, 4H);
3.99(s, 2H); 4.54(t, 2H); 7.26(m, 3H)7.68
(m, 1H)
4 1.13(t, 3H); 1.46(m, 2H); 1.95(m, 4H); 2.52
(t, 2H); 2.79(m, 4H); 3.34-3.81(m, 8H); 4.05-4.19
(2t, 4H); 6.20(m, 1H); 7.0-7.5(m, 6H)
5 D.sub.2 O: 0.93(t, 3H); 1.3-2.0(m, 6H); 2.6(m, 2H);
2.95(m, 4H); 3.17-3.62(m, 8H); 4.11(m, 4H); 7.1
(m, 3H); 7.4(m, 1H); 7.87(s, 1H); 7.97(s, 1H)
6 1.13(t, 3H); 1.33(t, 3H); 1.93(m, 6H); 2.6
(t, 2H); 2.8(m, 4H); 3.35-3.82(m, 8H); 4.07-4.4
(m, 6H); 7.1-7.25(m, 3H); 7.5(m, 1H); 7.85(s, 2H)
(m, 3H)
______________________________________
Pharmacological Activity
The products which are the subject of the present invention are potent
antihistaminics which are characterised in that they are free from
sedative effects, in contrast to most known antihistaminics.
Antihistaminic Activity "In Vivo"
The antihistaminic activity was studied by determining the protection
against the mortality caused by the product 48/80 in rats. This trial was
performed according to the technique described by C. J. E. Niemegeers et
al. (Arch. Int. Pharmacodyn., 234, 164-176 (1978). The products which are
the subject of the present invention are administered to the rats by the
i.p. route. After 60 minutes, the compound 48/80 is administered (0.5
mg/kg, i.v.). The protective activity is defined as the survival of the
rats 4 hours after the i.v. injection of the 48/80.
The activity of the products is studied at several doses in order to
determine the dose which is capable of protecting 50% of the animals
(ED-50).
Finally, the antihistaminic activity of the product of Example 1 is
indicated. This activity is compared with that of difenhidramine, a
reference antihistaminic.
______________________________________
Antihistaminic activity "in vivo":
Protection from 48/80-induced death
Example no. ED-50 (mg/kg, i.p.)
______________________________________
1 0.04
Difenhidramine
5.4
______________________________________
Sedative Effect: 1) Irwin Test
To study the absence of sedative effect of the products which are the
subject of the present invention, they were administered to rats by the
i.p. route and the behaviour of the animals was observed according to the
standards described in the S Irwin test (Science. 136, 123-128 (1962)).
The result obtained for the product of Example 1 is shown below in both
evaluations reflecting the sedative effect:
Pas.: Passivity, sedation, prostration. Quantitative evaluation between 0
and 3. They are performed 1, 2 and 3 hours after the treatment.
Atax.: Ataxia, the modifications of coordination in movement are evaluated.
The are evaluated between 0 and 3. They are performed 1, 2 and 3 hours
after the treatment.
The results of the study of the sedative effect of the product of Example 1
of the present invention, are summarised below by way of example. This
activity was compared with that of difenhidramine, a reference
antihistaminic. This product exhibits a very weak sedative effect, unlike
difenhidramine which proved toxic at a dose of 80 mg/kg, i.p., due to
depressive effects on the CNS.
______________________________________
Sedative effect: 1) Irwin Test
Dose Effect
Example no. (mg/kg) pas. Atax.
______________________________________
1 (80) 0 0.2
Difenhidramine
(40) 0 0.9
(80) Toxic
______________________________________
Sedative Effect: 2) Potentiation of Pentobarbital-Induced Duration of Sleep
The study of the potentiation of the duration of sleep due to pentobarbital
was performed according to the method described by L. E. Allen et al.
(Arz. Forsch. 24, (6), (1974)). The studied products were administered
orally. Sodium pentobarbital (35 mg/kg, s.c.) was administered one hour
later and the length of time before the animals awoke was determined. The
duration of sleep was compared with a control group of animals treated
only with sodium pentobarbital.
To complete the studies which demonstrate the absence of sedative effect of
the products which are the subject of the present invention, the activity
of one of the products (Example 1) was compared, in this test, with the
reference antihistaminic, difenhidramine. The results of this test with
Example 1 and difenhidramine are presented below. It is evident that
difenhidramine significantly potentiates the duration of sleep at a dose
of 20 mg/kg, whereas Example 1 does not potentiate the
pentobarbital-induced duration of sleep even at 160 mg/kg, the maximum
dose tested.
______________________________________
Sedative effect: 2) Potentiation of
pentobarbital-induced duration of sleep
Dose Potentiation of
Example no. (mg/kg, p.o) duration of sleep
______________________________________
1 80 8% N.S.
160 1% N.S.
Difenhidramine
10 22% N.S.
20 38% *
______________________________________
N.S.: Not significant
*: Significant difference with the control group (p < 0.05)
A specific pharmaceutical dosage form of the derivatives which are the
subject of the present invention, will be indicated below by way of
example.
______________________________________
Tablets
Formula per tablet
______________________________________
Compound of Example 1
10.00 mg
Lactose 54.00 mg
Corn starch 26.60 mg
Microcrystalline cellulose
18.00 mg
Polyvinylpyrrolidone
6.00 mg
Croscarmellose sodium
3.60 mg
Colloidal silicon dioxide
0.60 mg
Magnesium stearate 1.20 mg
120.00 mg
______________________________________
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